Update on diagnostic and therapeutic strategies for antibody-mediated rejection in kidney transplantation

Table 1 Chronology of antibody mediated rejection advancements and defining developments

Year	Key developments
1964[11]	Recognition of immediate kidney rejection caused by pre-existing antibodies
1970[12]	Emergence of obliterative vascular lesions in recipients with de novo DSA, leading to poor transplant outcomes
1990[13]	Characterization of AMR through a three-factor framework: (1) Impaired graft function; (2) Presence of neutrophils in peritubular capillaries; and (3) Detection of class I HLA antibodies, independent of conventional T-cell-mediated rejection
1993[14]	Confirmation of the role of DSA in rejection with C4d deposition in PTC
1997[15]	Banff consensus establishes histological guidelines for kidney transplant biopsies: AMR is determined as rejection partially or fully attributed to anti-donor antibodies, categorized as hyperacute (immediate) or accelerated acute (delayed reaction)
2001[16-17]	Classification of AMR. Chronic rejection is defined as progressive deterioration of renal function, marked by hypertension and proteinuria beyond three months post-transplant: C4d staining in PTC distinguished AMR from non-specific CAN. Cases lacking detectable antibodies are classified as “suspicious for AMR.”
2005[18]	Banff classification revised to replace CAN with chronic active AMR. Discovery of AT1R-activating antibodies. Isolated tubulitis under the borderline category
2007[19]	Banff developed grading for PTC inflammation, Focal C4d, C4d scoring, and interpretation of C4d deposition absent overt histological rejection. ti score. Grading of zero-time and protocol biopsies
2009	Subclinical AMR. Creation of Banff Working Groups
2013[20]	Major revision of AMR definition: C4d staining is no longer an absolute necessity; microvascular inflammation or validated GEP is used as an additional diagnostic marker. Cg1a scoring. HLA DSA testing by SA
2015	Specific reports for each organ. i-IFTA. Role of non-HLA-DSA
2017[21]	Banff incorporates C4d staining and molecular classifiers as surrogate indicators of DSA presence. AMR without anti-HLA DSA
2019[22]	Introduction of machine learning-based FFPE-based molecular diagnostics to refine AMR classification. FFPE-based molecular diagnostics
2021	Banff incorporated multi-omics approaches (genomics, transcriptomics, proteomics) to improve AMR detection
2023	Artificial intelligence-assisted digital histopathology was introduced for automated grading of AMR severity. Routine molecular diagnostics as a “companion criterion standard.” Open source analytic pipeline. Machine learning based biopsy contextualization
2025[23-25]	Banff further refines AMR classification with four advancements: (1) C4d and molecular classifiers remain key markers; (2) Single-cell RNA sequencing aids in identifying early AMR signatures; (3) Non-invasive biomarkers (circulating donor-derived cell-free DNA) validated for AMR monitoring; and (4) Personalized immunosuppressive strategies based on molecular profiling introduced

DSA: Donor-specific antibody; AMR: Antibody mediated rejection; HLA: Human leucocyte antigen; PTC: Peritubular capillary; CAN: Chronic allograft nephropathy; AT1R: Angiotensin receptor; GEP: Gene expression profiling; IFTA: Interstitial fibrosis and tubular atrophy; Cg: Chronic glomerulopathy; FFPE: Formalin-fixed paraffin- embedded; SA: Single antigen.